The invention relates to the conversion of xcex1,xcex2-unsaturated amides and esters to xcex1,xcex2-substituted amino amides, esters, and acids. More particularly, the invention relates to three-step converion processes employing an osmium-catalyzed aminohydroxylation step to produce xcex1,xcex2-hydroxysulfonamide or hydroxycarbamate amide or ester intermediates, a cyclodehydration step to produce an xcex1,xcex2-N-sulfonyl- or the xcex1,xcex2-N-carbamoylaziridine amides or esters and a regioselective nucleophilically induced ring-opening step to give the xcex1,xcex2-substituted amino- amides or esters.
One aspect of the invention is directed to a method for converting an xcex1,xcex2-unsaturated substrate to a blocked or unblocked xcex1,xcex2-substituted amino product. The xcex1,xcex2-unsaturated substrate may be an xcex1,xcex2-unsaturated amide or an xcex1,xcex2-unsaturated ester. The xcex1,xcex2-substituted amino product corresponds to the xcex1,xcex2-unsaturated substrate, i.e., it is an xcex1,xcex2-substituted amino amide or xcex1,xcex2-substituted amino ester. The xcex1,xcex2-substituted amino product may be either blocked or unblocked. The blocked xcex1,xcex2-substituted amino product includes a blocked amino group. The unblocked xcex1,xcex2-substituted amino product includes an unblocked amino group.
In the first step of the conversion, the xcex1,xcex2-unsaturated substrate is oxidized with a nitrogen source for making a racemic mixture of an xcex1,xcex2-hydroxy-amino intermediate. The xcex1,xcex2-hydroxy-amino intermediate includes a blocked amino group and corresponds to the substrate, i.e., it is an xcex1,xcex2-hydroxy-amino amide or an xcex1,xcex2-hydroxy-amino ester. Preferred nitrogen sources include carbamate and sulfonamide. In a preferred mode, the oxidation is a regioselective osmium-catalyzed aminohydroxylation. Then, the above xcex1,xcex2-hydroxy-amino intermediate is cyclodehydrated for producing an xcex1,xcex2-N-blocked-aziridine intermediate having an aziridine ring, the xcex1,xcex2-N-blocked-aziridine intermediate. The aziridne intermediate corresponds to the starting material, i.e., it is an xcex1,xcex2-N-blocked-aziridine amide or an xcex1,xcex2-N-blocked-aziridine ester. Then, the aziridine ring of the xcex1,xcex2-N-blocked-aziridine intermediate is opened with a nucleophile in a regioselective manner for making the blocked xcex1,xcex2-substituted amino product. Preferred nucleophiles are hydrocarbons having a nucleophilic moiety selected from a group consisting of thiol, alcohol, nitrile and amine. Finally, the amino group of the blocked xcex1,xcex2-substituted amino product is optionally unblocked to produce the unblocked xcex1,xcex2-substituted amino product. The amide or ester group of the blocked or unblocked xcex1,xcex2-substituted amino product may be hydrolyzed for forming a blocked or unblocked xcex1-substituted xcex2-amino acid.
Another aspect of the invention is directed to the synthesis of a library comprising a plurality of compounds using the above described method.
Another aspect of the invention is directed to a method for converting an xcex1-xcex2 unsaturated substrate to a racemic mixture of an xcex1-hydroxy-xcex2-amino regio-isomer product having a blocked amino group. The xcex1-xcex2 unsaturated substrate may be an xcex1-xcex2 unsaturated amide or an xcex1-xcex2 unsaturated ester. The xcex1-hydroxy-xcex2-amino regio-isomer product is formed by admixing a nitrogen source and a hydroxyl radical with the xcex1-xcex2 unsaturated substrate. The method is of a type which employs a reaction solution which includes osmium as a catalyst, The xcex1-xcex2 unsaturated amide substrate is present and soluble at a stoichiometric concentration within the reaction solution. The osmium is present and soluble within the reaction solution at a catalytic concentration. Preferred nitrogen source include sulfonamide and carbamate.
Another aspect of the invention is directed to a method for converting an xcex1-xcex2 unsaturated substrate to an asymmetric xcex1-hydroxy-xcex2-amino regio-isomer product having a blocked amino group. The xcex1-xcex2 unsaturated substrate may be an xcex1-xcex2 unsaturated amide or an xcex1-xcex2 unsaturated ester. The asymmetric xcex1hydroxy-xcex2-amino regio-isomer product is formed by admixing a nitrogen source, a chiral ligand, and a hydroxyl radical with the xcex1-xcex2 unsaturated substrate. The method employs a reaction solution which includes osmium as a catalyst. The xcex1-xcex2 unsaturated substrate is present and soluble at a stoichiometric concentration within the reaction solution. The osmium is present and soluble within the reaction solution at a catalytic concentration. Preferred nitrogen sources include sulfonamide and carbamate. The chiral ligand is selected for enantiomerically directing the addition of the nitrogen source and hydroxyl radical. In a preferred mode, the admixture occurs in a co-solvent mixture containing an organic component and an aqueous component.
Another aspect of the invention is directed to a method for converting an xcex1,xcex2-hydroxy-amino substrate having a blocked amino group to an xcex1,xcex2-N-blocked-aziridine product. The xcex1,xcex2-hydroxy-amino substrate may be an xcex1,xcex2-hydroxy-amino amide or an xcex1,xcex2-hydroxy-amino ester. The hydroxyl moiety of the xcex1,xcex2-hydroxy-amino substrate is activated with an activating agent for producing an activated xcex1,xcex2-hydroxy-amino intermediate having an activated hydroxyl moiety and an amino nitrogen. The activated xcex1,xcex2-hydroxy-amino intermediate corresponds to the substrate and may be an activated xcex1,xcex2-hydroxy-amino amide or an activated xcex1,xcex2-hydroxy-amino ester. Then, the activated hydroxyl moiety of the activated xcex1,xcex2-hydroxy-amino intermediate is displaced with the amino nitrogen by base promoted ring closure for forming the xcex1,xcex2-N-blocked-aziridine product.